ABSTRACT Hearing loss in children is one of only a few preventable chronic conditions that has lifelong consequences, affecting early language development, school achievement, and future employment. Hearing loss is particularly common in rural Alaska Native children, often related to infection. However, little is known about risk factors driving infection-related hearing loss, and likely genetic, nutritional, and environmental risk factors all contribute. Respiratory illness in Alaska Native children, which often leads to recurrent ear infections, has been associated with the ?CPT1A arctic variant.? This single nucleotide variant in the carnitine palmitoyltransferase 1A (CPT1A) gene, required for fatty acid metabolism, is the most common form of CPT1A found in the Yup?ik and Inupiaq Alaska Native people. Two copies of the CPT1A arctic variant are associated with increased risk of respiratory illness, ear infections, and infant mortality. These health effects prompted the State of Alaska to begin universal DNA-based newborn screening for the CPT1A arctic variant in 2016. In addition to genetic risk factors for recurrent infection, nutritional influences in Alaska Native people are shifting as Western diets become increasingly common when traditional subsistence foods, rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), historically predominated. Lastly, environmental disparities are common in rural Alaska Native communities, including lack of running water in 27% of homes, household crowding, and poor indoor air quality due to wood-burning stoves. The objective of this study is to define the link between the CPT1A arctic variant and childhood hearing loss, and to characterize how environmental and nutritional factors modify this effect on hearing. We will leverage a unique NICHD-funded (1R01HD089951-01) prospective cohort study in northern and western Alaska that will begin enrolling expectant Alaska Native mothers in early 2020 and follow children through age two to assess overall health effects of the CPT1A arctic variant. This proposed study will partner with the NICHD cohort to evaluate, for the first time, underlying risk factors for hearing loss using a multilevel approach incorporating genetic, nutritional, and environmental influences. In Aim 1, we will characterize the relationship between the CPT1A arctic variant and hearing loss in Alaska Native children. We hypothesize that two copies of the CPT1A artic variant will increase the risk of infection-related hearing loss by 70%. In Aim 2, we will evaluate the impact of prenatal and postnatal exposure to traditional subsistence foods and environmental risk factors on the risk of hearing loss in Alaska Native children. We hypothesize that decreased exposure to traditional foods, measured with an n-3 PUFA biomarker, will be associated with an estimated 70% increase in risk of infection-related hearing loss, and environmental factors will increase risk of infection-related hearing loss by an estimated 60%. These factors will modify the association between CPT1A and risk of hearing loss. Our results will help to develop future interventions to reduce childhood hearing loss, an important health disparity in Alaska Native children, leading to improved health and socioeconomic outcomes.